Generally, antifungal agents are used for the treatment of superficial mycosis (trichophytosis, tinea versicolor, cutaneous candidiasis etc.). In recent years, therapeutic agents for tinea pedis such as luliconazole, amorolfine, lanoconazole and the like, which have a superior anti-Trichophyton activity, and therapeutic agents for tinea unguium such as terbinafine and itraconazole have been clinically applied. Nevertheless, the number of patients has not decreased, and the number of domestic patients with tinea pedis is estimated to be 25 million and that of domestic patients with tinea unguium is estimated to be 12 million.
Normally, the treatment of tinea pedis takes 4 weeks. However, the necessity of 4-month topical treatment for complete cure has been reported. When subjective symptoms such as flare, itch and the like disappear, patients cease treatment on self-judgment, which permits fungi present in the affected part to grow and often cause recurrence or relapse. Furthermore, reinfection with Trichophyton unleashed by family or patients themselves is considered to also prevent the number of tinea pedis patients from decreasing. Therefore, the development of an external antifungal agent which completely cures tinea pedis by application for a short period of time and causes less relapse has been desired.
Among the superficial mycosis, tinea unguium is particularly intractable, and commercially available external antifungal agents are not expected to penetrate thick nail plates. Therefore, oral antifungal agents such as terbinafine, itraconazole and the like are generally used for the treatment. Since the treatment requires oral administration of the medicament for at least 3 months, medication compliance of the patients is low. Moreover, while many of the tinea unguium patients are persons of middle or advanced age or elderly persons, patients with pre-existing disease such as diabetes and the like often interrupt or cease treatment due to side effects of oral preparation (e.g., hepatopathy, gastrointestinal disorder and the like) or drug interaction. These make it difficult to completely cure tinea unguium and cause many incidents of recurrence. Hence, an antifungal agent highly effective against tinea unguium by topical application free from systemic side effects and drug interaction is demanded in clinical practice.
Since Trichophyton parasitizes in the keratinous tissues of stratum corneum layer, nail and hair, for an antifungal agent to exhibit a superior treatment effect, (1) superior anti-Trichophyton activity, (2) good penetrability and accumulability in stratum corneum, and (3) less decrease in the activity due to adsorption to keratin, a keratinous component, are required. Many of the commercially available superficial mycosis therapeutic agents are superior in the anti-Trichophyton activity and penetrability and accumulability in the stratum corneum, but show high adsorbability to keratin, as a result of which the activity decreases in the stratum corneum layer (see, for example, non-patent document 3). This is considered to be one of the reasons why a treatment by application of commercially available antifungal agents cannot cure tinea pedis or tinea unguium in a short time.
Inflammation, inflammation causing allergic disease and allergic reaction are generally divided into type I to type IV. In type I, inflammation and allergic reaction mainly in mastocytes are induced, as observed in allergic rhinitis, urticaria, pruritus and the like. Such immediate phase inflammation and allergic reaction are induced by chemical mediators such as histamine, leukotriene and the like, which are released from mastocytes, and anti-histamine drugs and chemical mediator-free suppressants and the like show treatment effects. In the late phase reaction following the immediate phase, intradermal infiltration of many eosinophils to occur to further aggravate inflammation. While type IV reaction is seen in diseases such as atopic dermatitis, contact dermatitis, psoriasis and the like, the treatment effects of anti-histamine drugs and chemical mediator-free suppressants are limited, and therefore, steroids are used as main therapeutic drugs. In addition, immunosuppressants such as cyclosporine, tacrolimus and the like show treatment effects against these diseases. However, those medicaments show various side effects. Steroids cause side effects such as infections, skin atrophy, diabetes and the like. Tacrolimus causes side effects such as severe skin irritation and the like in atopic dermatitis patients (see, for example, non-patent document 1). In consideration of the above, the development of a safer anti-inflammatory agent or antiallergic agent for inflammation and allergic reactions of type I, type IV and the like has been desired.
While compounds having an azolyl group such as triazolyl group, imidazolyl group and the like and a hydrazone structure in a molecule have been reported (see, for example, non-patent document 2 and patent documents 1 to 3), they have different structures of —N(R1)(R2) in the formula (I) from that of the present invention. Moreover, usefulness as an antifungal agent, anti-inflammatory agent or antiallergic agent is not described.                [patent document 1] JP-A-63-227586        [patent document 2] JP-A-6-161136        [patent document 3] WO 2004099371        [non-patent document 1] Dermatologic Therapy, 19(2), 118-126, 2006        [non-patent document 2] Heterocycles, 23(9), 2183-2186, 1985        [non-patent document 3] Antimicrobial Agents and Chemotherapy, 46(12), 3797-3801, 2002        